1. Field of the Invention
The invention relates to the field of medical therapy and to systems and methods of enhancing delivery of therapeutic agents to targeted tissue via particle radiation bombardment and/or systems and methods for guiding delivery of particle radiation via post treatment imaging of the target tissue.
2. Description of the Related Art
Cancer remains one of the more challenging diseases to develop effective therapies for. One fundamental difficulty is the ability to effectively deliver cancer drug activity to the tumor while avoiding activity of the cancer drug on non-cancerous tissue. The ideal therapeutic drug would selectively reach the desired tumors target without negatively affecting non-cancerous tissue. However, existing regimens of chemotherapy and other targeted cancer therapies fall short of this ideal. For example, in some instances only between one to ten parts per one hundred thousand of intravenously administered monoclonal antibodies targeting cancer cells reach their intended targets.
Two main approaches or goals have been used recently to attempt to preferentially concentrate therapeutic agents at tumor sites. A first approach is to increase the targeting selectivity of cancer drugs. A second is to attempt to overcome biological barriers that inhibit cancer drugs from effectively reaching their intended targets, e.g. tumors.
Targeting mechanisms can be generally divided into two main groups: passive and active mechanisms. One well known passive targeting mechanism is referred to as enhanced permeation and retention (EPR). EPR exploits the physiological phenomenon that capillaries at the site of infection, inflammation and solid tumors often have a compromised barrier function, facilitating extravasation and protracted lodging of drug carriers. Thus, therapeutic agents with prolonged circulation times would be expected to be preferentially targeted to the tumor area with respect to non-cancerous tissue. However, depending on the surface characteristics of drug carriers, the carriers can be taken up by the reticuloendothelial system (RES) rather than the tumor tissue, resulting in relatively short circulation time. In general, carriers exhibiting hydrophobic surfaces tend to be absorbed by the RES cells of the liver and to a lesser degree by those of the spleen and lungs. Accordingly, a coating of hydrophilic compounds, such as polyethylene glycol (PEG) can reduce RES sequestration and significantly extend circulatory half life.
Active targeting mechanisms can include the molecular targeting of drug carriers by combining or conjugating the active recognition aspects of tumor specific molecules to the surfaces of drug carrier particles. For example, tumor specific antigens have been used to direct nano particles to angiogenic endothelium, for example to target αvβ3 integrins perfluorocarbon nano emulsions for MRI imaging of neovasculature and anti-angiogenesis therapy for melanoma and colon adenocarcinoma.
Another type of active, site directed drug delivery mechanism uses some form of external energy to direct the delivery of drug carriers. Examples of directed energies that have been used experimentally to control the pharmacokinetics and activation of cytotoxic drugs include magnetic fields, photonic radiation, heat, and ultrasound. For example, by applying a suitable magnetic field to specific regions of tissue, capsules loaded with magnetic materials can be driven preferentially to a tissue area. Another example of site directed targeting is induction of adhesion proteins in tumor microvasculature by ionizing radiation which is then used as antigenic targets for site specific drug delivery to tumor blood vessels. Other examples include the use of focused ultrasound to burst lipid encapsulated microbubbles and localized thermal ablation of cancer regions with near infrared photonic radiation.
However, a limitation of such directed energy mechanisms are that they exhibit poor tissue penetration and poor localization. For example, photonic radiation begins delivery energy to the surface of the tissue and the delivered energy tends to drop off exponentially with passage through the tissue. This can result in misdirected drug delivery due to the non-optimal dose profile of the radiation. Thus it will be understood that there exists a need for improved systems and methods of effectively targeting cancer drugs to cancer cells while reducing undesired effects on healthy tissue. There is also a need to more precisely identify cancerous tissue and confirm delivery of therapy thereto.